Endometrial cancer affects more than 40,000 women per year. The incidence of endometrial cancer is rising as life expectancy increases and as key risk factors, including obesity, becomes more prevalent. Long-lasting exposure to estrogen with a lack of opposing progesterone is highly associated with endometrial carcinoma. Progesterone is a hormone that antagonizes the growth-promoting properties of estrogen in the uterus. Progesterone therapy has been shown to be effective in preventing endometrial cancer as well as controlling growth of the endometrium. However, the effectiveness of progestins for women with endometrial cancer, is less clear. There is increasing evidence that steroid hormone receptors act in partnership with other transcription factors to potentiate or inhibit its action. We have shown that one member of the forkhead family of transcription factors, FOXO1 can associate with the progesterone receptor (PR) and influence its function. FOXO1 is a transcription factor that is highly expressed in the endometrium and has important roles inhibiting cell proliferation as well as inducing differentiation and apoptosis. FOXO1 protein expression is significantly decreased and even lost in endometrial cancer. This study proposes to investigate the molecular mechanisms associated with the PR/FOXO1 partnership in regulating genes that are inhibitory to cell proliferation and promoting apoptosis. The restoration of FOXO1 by inhibiting the pathway that leads to degradation of this protein in endometrial cancer could potentiate progestin therapy and thus be a more effective treatment for the progression of the disease. The potentiation of PR activity through an association with FOXO1 may provide a new opportunity for the development of combinatorial therapies. In addition, we propose that the loss of FOXO1 is an early event in endometrial neoplasia and could be used as a diagnostic marker for the early detection of endometrial cancer. PUBLIC HEALTH RELEVANCE: Endometrial cancer affects more than 40,000 women per year and its incidence continues to rise. This study proposes to identify the forkhead family of transcription factors, specifically FOXO1, as an early marker for endometrial cancer. In addition, the restoration of FOXO1 in endometrial tumors could potentiate progestin therapy and thus be a more effective treatment for the progression of the disease, providing a new opportunity for the development of combinatorial therapies.